T-cell prolymphocytic leukemia

What every physician needs to know:

T-cell prolymphocytic leukemia (T-PLL) is a rare, usually aggressive T-cell malignancy. Like many of the other T-cell lymphomas and leukemias, it is comprised of malignant post-thymic T-cells. The most common presenting features are a markedly elevated lymphocyte count, often with a rapid doubling time, and splenomegaly, although a subset of patients may present with an asymptomatic lymphocytosis. As such, it must be distinguished from more common B-cell malignancies: chronic lymphocytic leukemia, B-cell prolymphocytic leukemia, splenic marginal zone lymphoma, and hairy cell leukemia, as well as other T-cell disorders such as the human T-lymphotropic virus type 1 (HTLV-1) lymphomas, large granular lymphocytic leukemia, lymphoblastic lymphoma, and Sezary syndrome. Most patients with T-PLL will have concomitant lymphadenopathy, with rash and other cytopenias being common.

The prognosis is generally poor with the best therapeutic activity reported with alemtuzumab alone or alemtuzumab in combination with chemotherapy such as fludarabine or pentostatin. Remissions are often short lived with these treatments; however, long term remissions are reported with allogeneic stem cell transplantation.

Are you sure your patient has T-cell prolymphocytic leukemia? What should you expect to find?

You would expect to find:

Lymphocytosis

Splenomegaly

Lymphadenopathy

Rash

Hepatomegaly

Thrombocytopenia

Anemia

Beware of other conditions that can mimic T-cell prolymphocytic leukemia:

Other diseases that can present with a similar lymphocytosis include:

Chronic lymphocytic leukemia

B-cell prolymphocytic leukemia

Splenic marginal zone lymphoma, and hairy cell leukemia

HTLV-1 lymphomas

Large granular lymphocytic leukemia

Lymphoblastic leukemia/lymphoma

Sezary syndrome.

Which individuals are most at risk for developing T-cell prolymphocytic leukemia:

T-PLL is very rare representing about 1% of all T-cell malignancies in the United States. T-PLL usually presents in adults with a slight male preponderance. Individuals with ataxia telangiectasia are at increased risk of developing T-PLL. There are no known environmental risk factors.

What laboratory studies should you order to help make the diagnosis and how should you interpret the results?

HTLV-1 serology if adult T-cell leukemia/lymphoma (ATL) is on differential

What imaging studies (if any) will be helpful in making or excluding the diagnosis of T-cell prolymphocytic leukemia?

Computed tomography scan of the chest, abdomen, pelvis

The role of positron emission tomography/computed tomography (PET/CT) is unclear

If you decide the patient has T-cell prolymphocytic leukemia, what therapies should you initiate immediately?

Definitive therapy should be initiated as soon as the diagnosis is confirmed for patients with symptomatic disease. For asymptomatic patients with a lymphocytosis, close observation may be appropriate. While there is no universal standard approach, alemtuzumab is the most active agent either alone or in combination with chemotherapy.

More definitive therapies?

While there is no universal standard approach, alemtuzumab is the most active agent either alone or in combination with chemotherapy. Alemtuzumab, administered intravenously, is the single most active agent with response rates of 90% with complete remission rates of approximately 80%. The activity of the drug is significantly diminished when administered subcutaneously. Long term remissions are reported with allogeneic stem cell transplantation as consolidation of first or later remission. Pentostatin and nelarabine are also active drugs in this disease for patients who do not respond to alemtuzumab, though fewer than half of patients respond to these therapies and the median time to progression is short.

What other therapies are helpful for reducing complications?

Other therapies:

Prophylactic measures to prevent tumor lysis syndrome

Prophylactic antimicrobials when using alemtuzumab

Monitoring for Cytomegalovirus (CMV) reactivation with use of alemtuzumab

What should you tell the patient and the family about prognosis?

The prognosis is often poor with median survival measured in months to several years. However, with this aggressive disease, therapy needs to be started promptly. In suitable patients, human leukocyte antigen (HLA) typing of siblings should be done, for possible allogeneic stem cell transplantation, as this could be a potentially curative therapy if remission is achieved.

"What if" scenarios.

The key to proper management is a correct diagnosis, as the management and prognosis of similarly presenting B-cell processes (acute lymphoblastic leukemia, HTLV-1 associate lymphomas, Sezary syndrome, and large granular lymphocytic leukemia) is markedly different.

Pathophysiology

T-PLL is a malignancy of post thymic T-cells with the cytogenetic abnormalities listed above.

Ultimately the diagnosis is suspected by the above clinical presentation, with peripheral blood smear analysis showing a proliferation of prolymphocytes with immunohistochemical analysis most often showing expression of CD2, CD5, CD7, and cytogenetics showing an inv (14) (q11;q32). Other cytogenetic abnormalities are also reported. As is seen with other T-cell lymphomas, normal T-cell antigens may be down regulated such as surface CD3, and a clonally rearranged T-cell receptor is often seen. TdT and CD1a should be negative and CD4 and CD8 are variably expressed.

What other clinical manifestations may help me to diagnose T-cell prolymphocytic leukemia?

History of autoimmune disease should prompt an evaluation for large granular lymphocytic leukemia as an alternative diagnosis.

Origins from an area endemic for HTLV-1 should prompt serologic testing for HTLV-1 as an alternative diagnosis.

History of skin rash predating the lymphocytosis, or rash as a dominant feature with a lower degree of lymphocytosis should prompt a skin biopsy and evaluation to exclude Sezary syndrome as an alternative diagnosis.

What other additional laboratory studies may be ordered?

Patients with T-PLL are HTLV-1 negative.

Malignant lymphocytes in patients with Sezary syndrome usually mark as CD4+/CD7- and CD4+/CD26-, which may aid in distinguishing them from T-PLL.

CD52 is the target of alemtuzumab and it is reasonable to test prior to initiating therapy, if time permits. HLA typing should be performed early on in patients potentially suitable for allogeneic stem cell transplantation.

Wiktor-Jedrzejczak, W, Dearden, C, de, Wreede. "Hematopoietic stem cell transplantation in T-prolymphocytic leukemia: A retrospective study from the European Group for Blood and Marrow Transplantation and the Royal Marsden Consortium". Leukemia.

[Registry study providing proof of principle on the role of allogeneic stem cell transplantation.]

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